The proposed project is a 5-year competing renewal of "Treatment Evaluation in Premenstrual Syndrome Patients". The purpose of these studies is to a) determine the efficacy of selected anti-depressant, hormonal and anxiolytic medications in treatment of premenstrual syndrome (PMS) and b) determine the course and stability of premenstrual symptoms and the extent to which they continue to impact the quality of life. These studies relate to our working hypothesis that the mood and behavioral changes of PMS derive from central effects, possibly an altered CNS sensitivity to gonadal-adrenal steroids. The specific aims are as follows: 1) Compare a serotonin-selective antidepressant versus a noradrenergic anti-depressant to determine their effects in PMS treatment; 2) Identify the effects of reduced A ring metabolites of progesterone (allopregnanolone and pregnanolone) in PMS subjects following oral micronized progesterone dose; 3) Complete the current study comparing the efficacy or oral micronized progesterone and the benzodiazepine alprazolam, both of which are postulated to potentiate GABA transmission through binding to the GABA receptor complex, although at different binding sites; 4) Determine the course and stability of PMS symptoms following diagnosis and the impact of these symptoms on the quality of life. The methods to achieve these aims are 1) conduct a definitive randomized, double-blind, placebo-controlled study of Sertraline and Desipramine in PMS patients; 2) measure progesterone metabolites following double- blinded oral progesterone dose and correlate metabolite levels behavioral measures and treatment responses; 3) complete the current oral progesterone/alprazolam/placebo efficacy study in the first continuation year with sufficient sample size for definitive results; and 4) conduct a long-term follow-up study of women diagnosed with PMS. PMS is a complex, poorly understood, menstrually-related disorder reported at severe levels by 5-10% of cycling women. The sheer number of these women in the prime ages of life would indicate that PMS is a significant health problem that merits development of effective treatments. Additionally, the proposed studies will contribute to understanding of neuroendocrine effects in PMS and the identification of subgroups in the PMS population. Information on the course of PMS symptoms is important for understanding its occurrence and chronicity, which reduces the quality of life and affects the use of costly medical resources.